Despite excellent 1 yr. outcomes, long-term kidney allograft survival rates have not improved. Late allograft loss is increasingly attributed to cumulative effects of early/ongoing immunological injury that may be clinically silent. Thus, conventional immunosuppression (IS) and anti-rejection therapy are often insufficient to prevent immunological damage that leads to late allograft loss. Clinical markers, and even protocol Bxs, cannot predict outcomes accurately enough to individualize IS - highlighting the importance of a predictive non-invasive biomarker. Regulatory B cells (Bregs) and effector B cells (Beff) can profoundly influence immune responses through their respective expression of anti- vs. pro- inflammatory cytokines. While Bregs and Beff lack specific phenotypes, we showed that human Breg vs. Beff activity is best defined by the ratio of IL-10/TNF? . Transitional B cells (TrB), and particularly the most immature T1 subset (?T1B?), exhibit the highest IL-10/TNF? ratio and the most potent Breg activity. We examined 235 kidney transplant patients who had for-cause or 3m and 12m protocol biopsies (Bxs). A low T1B IL-10/TNF? ratio at 2-4 mos was strongly predictive of late acute rejection (AR; clinical or sub-clinical) by 6-12 mos. Altogether, ~50% of our patients have a low index T1B ratio (mos 2-4), and of these, ~70% develop recurrent or de novo late AR vs. 5% for those with a high ratio. Indeed, this biomarker allows us to identify patients at 2-4 mos with high immunological risk to develop late AR, IF+inflammation (12 mos), increased sCreatinine (24 mos), and graft loss (40 mos), with enough lead-time to pre-emptively increase IS to inhibit the alloimmune effector response, and thereby prevent ensuing rejection and irreversible damage. In this R34 proposal, we will plan all aspects of a phase 2 interventional trial in which adult renal allograft recipients at high immunological risk based on the T1B biomarker at 2-4 mos, will be randomized to receive either standard of care (SOC), or SOC + anti-TNF. Anti-TNF is a potent immune-modulating therapy, and pilot studies suggest it might alter B cell cytokines to promote their regulatory, and inhibit their inflammatory, activity. In AIM 1 we will plan a randomized clinical trial of SOC vs. SOC + anti-TNF in high-risk patients. At the same time, we will compare clinical outcomes in high and low risk patients being treated with SOC, to validate the biomarker in this interventional trial. In AIM 2 we will plan sequential immunological analysis to determine whether the T1B IL-10/TNF? ratio changes with anti-TNF therapy, identify the magnitude and duration of this change, and determine whether this correlates with clinical response and other immunological parameters. We hypothesize that using the T1B IL-10/TNF? ratio to guide treatment of high-risk patients with anti-TNF will improve their transplant outcomes.